The present invention is directed to apparatus for delivering air-borne substances and, more particularly, to apparatus which deliver such substances from pulsatile devices yet do so in a uniform (i.e., non-pulsatile) manner.
Metered dose inhalers (xe2x80x9cMDIsxe2x80x9d) have been the preferred method of delivery of drugs for treatment of asthma and other diseases of the respiratory tract for over twenty years. Human beings open their mouths voluntarily to inhale a therapeutic bolus, while animal models used in inhalation toxicology must be tested using continuous flow systems. FDA requirements and good laboratory practices (GLP) specify that a uniform concentration of the drug be maintained, although the output from conventional MDIs is pulsatile. Additionally, the Montreal Convention requires that existing MDI formulations be replaced by more environmentally benign formulations, using new propellant mixtures to replace chlorofluoro hydrocarbons. FDA regulations also require that each new formulation be tested as if it were a new drug, creating a major need for more efficient toxicity testing of MDI devices.
Recently, pharmaceutical companies have developed a large number of biologically active peptides, many of which can be produced in bulk using genetically modified bacteria or animals such as goats. Although many such peptides degrade rapidly when ingested, studies have shown that when they are delivered to the alveoli they cross the lung/blood barrier without major degradation. Thus, aerosol delivery to the deep lung is the method of choice for many promising new peptide pharmaceuticals, many of which must be tested by studies in at least two models prior to initiation of clinical trials.
When a new pharmaceutical is being produced in the laboratory, it remains very expensive, even if scale-up following satisfactory toxicity testing is expected to reduce the ultimate price to consumers. Due to this expense, whenever possible the quantity of pharmaceutical (or toxicant) to be tested should therefore be minimized.
Flow past, nose-only exposure chambers have been developed for drug testing, and these have increasingly replaced whole body exposure chambers for pharmaceutical work. The flow rate required (typically 30 liters per minute (LPM)) is an order of magnitude less than that for whole body chambers, reducing toxicant consumption ten-fold. Current MDI aerosol generators, however, are rather inefficient in aerosol delivery. Typical delivery values range from 10% to 20%. Thus, a further three or four fold reduction in toxicant consumption can be expected to be achieved if delivery efficiencies are increased to the 60-80% range typical of most aerosol delivery systems used in animal exposures. Even a two-fold improvement would be significant.
This is particularly true with MDIs. The plume from a MDI spreads out to about three inches in diameter, and larger particles within the plume have a trajectory of about one foot. Thus, problems are encountered due to particle loss by impaction unless an adequate trajectory is allowed. A further problem is that an MDI produces a sudden burst of aerosol, or pulsatile flow, whereas the nose-only exposure chambers which meet GLP and FDA regulations must have a steady or uniform aerosol concentration delivered to them.
Existing systems attempt to solve the problems of plume impaction and pulsatile output by firing the MDIs (singly or in groups of up to six at a time) into a chamber of diameter 18 inches or more. Such systems contain a mixing chamber wherein the MDI plume flows in a horizontal direction and the dilution air flows in a vertical direction. The cross-sectional area of such chambers is approximately 1500 sq. cm. Thus, a flow rate of 30 LPM (required for a nosexe2x80x94only chamber) represents a mean upward velocity of 20 cm/min, giving a three foot tall chamber a mean residence/mixing time of almost five minutes. Data demonstrate that this is ample to damp out the pulsatile effect of MDIs fired at five second intervals. The output from the system is very stable and is not discernibly pulsatile. No special effort is made to ensure thorough mixing of the dilution air (drawn upwards by the exhaust system) with the horizontal MDI plumes. The data suggest an elaborate mixing system is not needed for a system with long mean residence times.
A possible draw-back to this approach is that it couples a generator with a slow rise time (t90) of over ten minutes to a chamber with small internal volume and rapid rise time (approximately one minute). In addition, although the upward velocity of less than a cm/sec should be adequate to support particles of up to ten microns, most practical working generators employ linear velocities much higher than this to overcome the effects of turbulence in the mixing chamber. A review of available data on the efficiency of delivery of the existing systems suggests analytical to nominal (A/N) ratios between 0.1 and 0.2. These calculations are estimates, based on firing rates of the MDIs, nominal output per firing, and a 30 LPM flow-rate.
Consequently, there remains a need in the art for aerosol delivery systems which employ relatively rapid flow rates without the need for complex control systems to minimize pulsatile flow. An aerosol generating apparatus utilizing a much smaller diameter and coaxial flow of diluent air and MDI propellant should have a significantly reduced t90, and a greater efficiency of delivery.
It is one object of the present invention to provide systems which deliver aerosol materials from a plurality of pulsatile delivery devices.
It is another object of the invention to provide systems which deliver aerosol materials in a substantially uniform manner from a plurality of pulsatile delivery devices.
It is a further object to provide systems which deliver aerosol materials from pulsatile devices yet do not require involved systems for mixing air with the materials emitted by such devices.
It is yet another object to provide aerosol delivery systems having flow rates that closely match those employed in typical animal exposure chambers.
These and other objects are satisfied by the present invention, which provides apparatus and methods for uniform delivery of air-borne materials from pulsatile delivery devices by passing air and the emissions from such devices in a coaxial manner through a suitable mixing chamber. In preferred embodiments, the apparatus of the invention comprise a chamber defining an axis of air flow, a plurality of pulsatile delivery devices, actuator means in communication with the devices for selective actuation thereof, and air flow means for introducing air at a first end of the chamber and for flowing that air substantially along said axis. In accordance with the invention, the pulsatile delivery devices are positioned at the first end of the chamber such that actuation of the devices emits an air-borne substance substantially along the axis of air flow.
The present invention further provides processes for delivering air-borne substances in a uniform manner. Preferred processes involve the use of an apparatus comprising a chamber defining an axis of air flow and a plurality of pulsatile delivery devices positioned at a first end of the chamber such that actuation of the devices emits an air-borne substance substantially along the axis. These processes comprise actuating at least one of the delivery devices and introducing air into the chamber at the first end thereof such that the air flows substantially along the axis.